Cycloisomerization between Aryl Enol Ether and Silylalkynes under Ruthenium Hydride Catalysis: Synthesis of 2,3-Disubstituted Benzofurans

Article abstract of DOI:10.1021/acs.orglett.7b00985

Metal-catalyzed cycloisomerization reactions of 1,n-enynes have become conceptually and chemically attractive processes in the search for atom economy, which is a key subject of current research. However, metal-catalyzed cycloisomerization between aryl enol ether and silylalkynes has not been developed. The ruthenium hydride complex catalyzed cycloisomerization between aryl enol ether and silylalkynes is reported to give benzofurans having useful functional groups, vinyl and trimethylsilylmethyl, on the 2- and 3-positions, respectively.

Full text of DOI:10.1021/acs.orglett.7b00985

Letter
pubs.acs.org/OrgLett
Cycloisomerization between Aryl Enol Ether and Silylalkynes under
Ruthenium Hydride Catalysis: Synthesis of 2,3-Disubstituted
Benzofurans
Shohei Ohno, Kohei Takamoto, Hiromichi Fujioka, and Mitsuhiro Arisawa*
Graduate School of Pharmaceutical Sciences, Osaka University, Yamada-oka 1-6, Suita, Osaka 565-0871, Japan
S
* Supporting Information
ABSTRACT: Metal-catalyzed cycloisomerization reactions of 1,n-enynes have
become conceptually and chemically attractive processes in the search for atom
economy, which is a key subject of current research. However, metal-catalyzed
cycloisomerization between aryl enol ether and silylalkynes has not been
developed. The ruthenium hydride complex catalyzed cycloisomerization between
aryl enol ether and silylalkynes is reported to give benzofurans having useful
functional groups, vinyl and trimethylsilylmethyl, on the 2- and 3-positions,
respectively.
ransition-metal-catalyzed cycloisomerization1 is an atom-
as well as pharmaceuticals and polymers.14 This method is
Teconomical method for the construction of complex suitable to synthesize a key intermediate for abexinostat, a
carbocyclic and heterocyclic frameworks,2 as, in cycloisomeriza-
broad-spectrum hydroxamic acid-based inhibitor of histone
deacetylase (HDAC) with potential antineoplastic activity.
We envisioned that an unprecedented cycloisomerization of
aryl enol ether and silylalkynes would be suitable methodology
to give substituted benzofurans. We prepared 2-(trimethylsilyl)-
ethynylphenyl vinyl ethers (1a) (Figure 1) and attempted a
tions, all atoms contained in the starting material are retained in
the final product. Hence, cycloisomerizations have received
much attention as perfect atom-efficient chemical trans-
formations.
Enol ethers have been widely used in not only polymer
synthesis but also organic synthesis owing to their electron-rich
double bonds.3 Although reactions4 of silyl enol ethers and
alkyl enol ethers have been greatly reported, reactions of aryl
enol ethers, a type of enol ether, have been limited to arylation
with Grignard reagents,5 radical or nitrative cyclizations,6 and
alkylation via C−H bond activation.7 Recently, several groups
reported transition-metal-catalyzed reactions of aryl enol ethers
to give oxygen-containing heterocycles. The Tanaka group
reported a rhodium-catalyzed enantioselective Alder−ene
reaction of 2-ethynylphenyl vinyl ether to give dihydrobenzo-
furan.8 Moreover, the Liu group reported gold-catalyzed
cyclization of 2-ethynylphenyl vinyl ether with external
nucleophiles to give benzo[b]oxepine.9 The Lin group reported
ruthenium-catalyzed10 cyclization of 2-ethynylphenyl vinyl
ether to give benzoxepine.11 In addition, the Li group reported
copper-catalyzed [2 + 2 + 1] annulation of 2-ethynylphenyl
vinyl ether with α-carbonyl alkyl bromides through C−Br/C−
H functionalization to give tricyclic heterocycles.12 The
Figure 1. 2-(Trimethylsilyl)ethynylphenyl vinyl ethers 1a.
variety of reaction conditions using conventional catalysts.8−13
However, we could obtain only a trace amount of the expected
benzofuran at most. We then treated 1a with not only
commercially available ruthenium hydrides, such as RuHCl-
(CO) (PPh3)3 and RuH2(CO) (PPh3)3, but also ruthenium
hydride A15 with a nitrogen-containing heterocyclic carbene
(NHC) ligand under various conditions (Figure 2 and Scheme
1). When 1a was treated with 5 mol % of RuHCl(CO) (PPh3)3
or RuH2(CO) (PPh3)3 in refluxing p-xylene, the expected
benzofuran 2a was obtained in low yields. The same reaction,
using a ruthenium hydride species A generated from the
Grubbs catalyst second generation II (Scheme 1), yielded the
corresponding 3-[(trimethylsilyl)methyl]-2-vinylbenzofuran 2a
in 84% yield (Scheme 2). Compound 2a could be a useful
synthon because it has a good functional group for further
chemical transformations on both the 2- and 3-positions of
benzofuran. Before examining these chemical transformations,
Furstner group reported a bond-making/bond-breaking cascade
̈
cycloisomerization/cross-coupling reaction of 2-ethynylphenyl
vinyl ether with Grignard reagents.13 All of these reactions are
organometallic-catalyzed reactions between aryl enol ethers and
alkynes, which has a proton or carbon. Here, we report an
unprecedented ruthenium hydride catalyzed cycloisomerization
of aryl enol ether and silylalkynes to yield 2,3-disubstituted
benzofurans having useful functional groups, vinyl and
trimethylsilylmethyl, on the 2- and 3-positions, respectively.
Benzofuran is present in numerous bioactive natural products
Received: April 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00985
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of One-Pot Olefin Isomerization/
Cycloisomerization
2a, yield (%) (from
entry
cat. (5 mol %)
solvent time(h)
3a)
1
2
RuHCl(CO)(PPh3)3 p-xylene
24
48
8
38
RuH2(CO)(PPh3)3
p-xylene
p-xylene
p-xylene
PhMe
15
32
84
55
0
a
3
I
a
4
II
1
a
5
II
4
Figure 2. Ruthenium carbene catalysts I−VII.
a
6
II
THF
4
a
7
a
III
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
1
83
62
trace
0
Scheme 1. Ruthenium Hydride A with the NHC Ligand
8
IV
1
a
9
V
1
a
10
VI
1
a
11
VII
1
69
0
12
RuClCp(PPh3)2
[IrCl(cod)2]2
Pd(OAc)2(PPh3)2
[Rh(cod)2BF4]
1
b
13
1
0
14
1
0
Scheme 2. Cycloisomerization of 2-Ethynylphenyl Vinyl
Ether 1a to give 2a
c
15
1
trace
a
b
1 equiv of CH2CHOSiMe3 was added. 25 mol % of AcOH was
c
added. 5 mol % of (rac)-binap was added.
Table 2. Effect of Alkyne Substituent on Reaction Yield
we decided to optimize reaction conditions for this cyclo-
isomerization as a one-pot reaction from the precursor 3a to 2a
through 1a.
A solution of 3a and RuHCl(CO) (PPh3)3 (5 mol %) in
dichloromethane was refluxed for 1 h, and 3a was converted to
1a, quantitatively. Without purification, cycloisomerization of
the obtained 1a was examined using several catalysts and
solvents (Table 1). As previously mentioned, when crude 1a
was treated with a commercially available ruthenium hydride,16
2a was obtained in 38%, 15%, or 32% yields (two steps),
respectively (Table 1, entries 1−3). In contrast, the same
reaction, using a ruthenium hydride species A generated from
the Grubbs catalyst second generation II (Scheme 2), yielded
the corresponding 3-[(trimethylsilyl)methyl]-2-vinylbenzofuran
2a in 84% yield (two steps) (Table 1, entry 4).17 These results
suggest that the NHC ligand on the ruthenium hydride species
is important for this cycloisomerization to proceed. We
determined that higher temperature, i.e., p-xylene refluxing
temperature, was necessary for this cycloisomerization (Table
1, entries 5 and 6). Next, we examined several ruthenium
carbene catalysts III−VII (Figure 2) and found that II and III
are suitable precatalysts for this cycloisomerization (Table 1,
entries 7−11). Control experiments using conventional
catalysts for 1,6-enyne cycloisomerization failed to yield 2a
(Table 1, entries 12−15).
entry
3
R
2, yield (%) (from 3)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
SiMe3
2a, 84
2b, 93
2c, 78
2d, 76
2e, 39
2f, 36
2g, 28
2h, 0
Si(i-Pr)3
SiMe2Bn
SiMe2Ph
CH3
t-Bu
3g
3h
3i
CH2OSiMe2-t-Bu
CH(OEt)2
Ph
2i, 0
with weaker electron-withdrawing groups on the alkyne, i.e.,
tert-butyl derivative 1f, silyloxymethyl derivative 1g, diethox-
ymethyl derivative 1h, and phenyl derivative 1i, did not take
part in this reaction very well; 1h and 1i were unchanged, and
1e, 1f, and 1g were converted to 2e, 2f, and 2g in 39%, 36%,
and 28% yields, respectively.
The effects of substituents on the benzene ring are
summarized in Table 3; the data show the scope and limitation
of this cycloisomerization. All of the substrates 3j−v were
subjected to the reaction conditions used in Table 1, entry 4
(Table 3). Compounds 1k−m,o−q,s−v, which have a
Based on these results, we next examined the effect of alkyne
substituents (Table 2). Trialkylsilyl, Si(i-Pr)3, SiMe2Bn, and
SiMe2Ph, derivatives 3b−d gave the corresponding cyclized
products in 93%, 78%, and 76% yields, respectively; the yield
difference is most likely the result of steric effects. Derivatives
B
DOI: 10.1021/acs.orglett.7b00985
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
prepared by our cycloisomerization between silylalkyne and
vinyl ether, may serve as a good synthon. Indeed, 2a was
efficiently converted to a key intermediate 718 for abexinostat, a
HDAC inhibitor with potential antineoplastic activity (Scheme
4).
Table 3. Effect of Benzene Substituent on Reaction Yield
Scheme 4. Synthesis of a Key Intermediate 7 for Abexinostat
entry
1
3
R
2, yield (%) (from 3)
3a
3j
H
2a, 84
2j, 45
2k, 80
2l, 71
2m, 55
2n, 54
2o, 75
2p, 70
2q, 87
2r, 61
2s, 84
2t, 81
2u, 74
a
2
3-Cl
3
3k
3l
4-Cl
b
4
5-Cl
a
5
3m
3n
3o
3p
3q
3r
6-Cl
a
6
3-Me
7
4-Me
a
8
5-Me
9
6-Me
Finally, we used NMR spectroscopy to obtain information on
the active ruthenium species in this cycloisomerization.19 We
b
10
3-OMe
4-OMe
5-OMe
6-OMe
4-CO2Et
11
12
13
3s
3t
1
compared the H and 31P NMR spectra of catalysts (II and A)
in p-xylene and the reaction mixture for the cycloisomerization.
For catalyst II, we observed signals for the benzylidene proton
3u
3v
b
c
14
2v, 54
1
at 19.7 ppm in the H NMR spectrum and tricyclohexylphos-
a
b
phine at 29.8 ppm in the 31P NMR spectrum. In the
cycloisomerization reaction mixture spectra, new catalyst A
peaks appeared within 10 min along with the cycloisomerized
compound 2a peaks, while with the ruthenium carbene catalyst
II and 1a peaks disappeared (Figure S1). These results and
those of the control experiments shown in Table 3 suggest that
this cycloisomerization proceeds via a ruthenium hydride A,
and a plausible reaction mechanism is drawn in Scheme S1.
In conclusion, we developed a ruthenium hydride catalyzed
cycloisomerization of 1, having (trialkylsilyl)alkyne and
arylvinyl ether moieties, to give 2,3-disubstituted benzofurans
2, having vinyl and (trimethylsilyl)methyl groups on the 2- and
3-positions, respectively, for the first time to our knowledge.
compound 2 is a useful synthon, and 2a was efficiently
converted to a key intermediate for abexinostat. This is also
another example of a nonmetathesis reaction using a ruthenium
carbene catalyst.20 These reactions will be of interest because
ruthenium carbene catalysts are widely used in functional
molecular synthesis.
10 mol % of I was employed. Reaction time was 8 h. Reaction time
c
was 3 h. 2v is an unstable compound.
substituent at the 4-, 5-, or 6-position, were converted to the
cycloisomerized product 2 in good yields. However, 1j,n,r, with
a substituent at the 3-position, were respectively converted to
2j,n,r in only 45%, 54%, and 61% yields (Table 3, entries 2, 6,
and 10). There were sharp contrasts between 1,2,3-
trisubstituted and 1,2,6-trisubstituted substrates, although
both have substituents at the ortho position. These results
suggest that some ruthenium hydride species react with the
silylalkyne moiety faster than the vinyl ether moiety on 1 in this
cycloisomerization (see the Supporting Information for the
proposed mechanism).
Chemical transformations of 2a were possible (Scheme 3).
For example, the vinyl group at the 2-position of benzofuran 2a
Scheme 3. Chemical Transformations of 2a
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00985.
1
Experimental procedures, characterization data, and H
and 13C NMR spectra for compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: arisaw@phs.osaka-u.ac.jp.
ORCID
was converted to the corresponding disubstituted alkene
derivative 4 or the hydroxyethyl derivative 5 via cross-
metathesis or hydroboration−oxidation in quantitative yields,
respectively. The (trimethylsilyl)methyl group at the 3-position
of 2a reacted with benzaldehyde in the presence of fluoride ion,
and the carbon−carbon bond-forming product 6 was obtained
in 90% yield. These results have shown that 2a, efficiently
Mitsuhiro Arisawa: 0000-0002-7937-670X
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.7b00985
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
xylene was heated at 40 °C for 10 min, 3a was added, and the whole
was refluxed for 1 h to give 2a in 40% yield.
(18) Vermer, E. J.; Sendzik, M.; Baskaran, C.; Buggy, J. J.;
Robinsonm, J. WO 2004092115, 2004.
(19) See the Supporting Information.
(20) For reviews, see: (a) Alcaide, B.; Almendros, P. Chem. - Eur. J.
2003, 9, 1258−1262. (b) Schmidt, B. Eur. J. Org. Chem. 2004, 2004,
1865−1880. (c) Arisawa, M.; Terada, Y.; Takahashi, K.; Nakagawa, M.;
Nishida, A. Chem. Rec. 2007, 7, 238−253. (d) Alcaide, B.; Almendros,
P.; Luna, A. Chem. Rev. 2009, 109, 3817−3858.
ACKNOWLEDGMENTS
■
This work was partially supported by a Grant-in-Aid for JSPS
(KAKENHI Grant No. JP A16H010260 in Precisely Designed
Catalysts with Customized Scaffolding, A262880510,
T15K149760, and T15KT00630) and the Platform Project
for Supporting in Drug Discovery and Life Science Research
(Platform for Drug Discovery, Informatics and Structural Life
Science) from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan (MEXT) (JST ACT-C Grant
No. JPMJCR12YM), and the Canon Foundation.
REFERENCES
■
(1) For selected recent reviews of the transition-metal-catalyzed
cycloisomerization, see: (a) Fang, G.; Bi, X. Chem. Soc. Rev. 2015, 44,
8124−8173. (b) Neff, R. K.; Frantz, D. E. Tetrahedron 2015, 71, 7−18.
(c) Furstner, A. Acc. Chem. Res. 2014, 47, 925−938. (d) Yamamoto, Y.
̈
Chem. Rev. 2012, 112, 4736−4769. (e) Fehr, C. Synlett 2012, 23, 990−
1006. (f) Aubert, C.; Fensterbank, L.; Garcia, P.; Malacria, M.;
Simonneau, A. Chem. Rev. 2011, 111, 1954−1993.
(2) For reviews of the transition-metal-catalyzed intramolecular
heterocyclization of enyne, see: (a) Harris, R. J.; Widenhoefer, R. A.
Chem. Soc. Rev. 2016, 45, 4533−4551. (b) Dorel, R.; Echavarren, A. M.
J. Org. Chem. 2015, 80, 7321−7332. (c) Furstner, A. Acc. Chem. Res.
̈
2014, 47, 925−938. (d) Obradors, C.; Echavarren, A. M. Acc. Chem.
Res. 2014, 47, 902−912. (e) Olszewski, T. K.; Bieniek, M.; Skowerski,
K.; Grela, K. Synlett 2013, 24, 903−919. (f) Braun, I.; Asiri, A. M.;
Hashmi, A. S. K. ACS Catal. 2013, 3, 1902−1907. (g) Zhang, D.-H.;
Zhang, Z.; Shi, M. Chem. Commun. 2012, 48, 10271−10279.
(3) (a) Hofmann, E.; Klimisch, H.-J.; Backes, R.; Vogelsang, R.;
Franz, L.; Feuerhake, R. In Ullmann’s Encyclopedia of Industrial
Chemistry; Wiley-VCH: Weinheim, 2011; Vol. 38, p 125. (b)
Comprehensive Polymer Science; Allen, G., Ed.; Pergamon Press: New
York, 1989; Vol. 3.
(4) Several recent examples of cycloisomerization. Au: (a) Hosseyni,
S.; Wojtas, L.; Li, M.; Shi, X. J. Am. Chem. Soc. 2016, 138, 3994−3997.
Fe: (b) Echeverria, P.-G.; Furstner, A. Angew. Chem., Int. Ed. 2016, 55,
̈
11188−11192.
(5) Iwasaki, T.; Miyata, Y.; Akimoto, R.; Fujii, Y.; Kuniyasu, H.;
Kambe, N. J. Am. Chem. Soc. 2014, 136, 9260−9263.
(6) (a) Hu, M.; Liu, B.; Ouyang, X.-H.; Song, R.-J.; Li, J.-H. Adv.
Synth. Catal. 2015, 357, 3332−3340. (b) Hu, M.; Song, R.-J.; Li, J.-H.
Angew. Chem., Int. Ed. 2015, 54, 608−612.
(7) Hatano, M.; Ebe, Y.; Nishimura, T.; Yorimitsu, H. J. Am. Chem.
Soc. 2016, 138, 4010−4013.
(8) Okamoto, R.; Okazaki, E.; Noguchi, K.; Tanaka, K. Org. Lett.
2011, 13, 4894−4897.
(9) Liu, J.; Liu, Y. Org. Lett. 2012, 14, 4742−4745.
(10) Cp(PPh3)2RuCl, Cp = η5-cyclopentadienyl.
(11) Chen, C.-R.; Lai, Y.-X.; Wu, R.-Y.; Liu, Y.-H.; Lin, Y.-C.
ChemCatChem 2016, 8, 2193−2196.
(12) Hu, M.; Song, R.-J.; Ouyang, X.-H.; Tan, F.-L.; Wei, W.-T.; Li,
J.-H. Chem. Commun. 2016, 52, 3328−3331.
(13) Echeverria, P.-G.; Furstner, A. Angew. Chem., Int. Ed. 2016, 55,
̈
11188−11192.
(14) Yeung, K.-S. Heterocycl. Chem. 2012, 29, 47−76.
(15) (a) Arisawa, M.; Terada, Y.; Nakagawa, M.; Nishida, A. Angew.
Chem., Int. Ed. 2002, 41, 4732−4734. (b) Terada, Y.; Arisawa, M.;
Nishida, A. Angew. Chem., Int. Ed. 2004, 43, 4063−4067. (c) Arisawa,
M.; Terada, Y.; Takahashi, K.; Nakagawa, M.; Nishida, A. J. Org. Chem.
2006, 71, 4255−4261.
(16) In the presence of vinyloxytrimethylsilane I was converted to
RuHCl(CO) (PCy3)2. See ref 15c.
(17) Although we tried a one-pot tandem sequence of double-bond
isomerization and subsequent cycloisomerization under various
conditions, the reaction was unsuccessful. For example, after a
solution of II (5 mol %) and vinyloxytrimethylsilane (1 equiv) in p-
D
DOI: 10.1021/acs.orglett.7b00985
Org. Lett. XXXX, XXX, XXX−XXX